Deciphering the genetics and mechanisms of predisposition to multiple myeloma

Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development.


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Sequence variants passing GATK filters have been deposited in the European Variation Achive, accession number PRJEB15197 (https://www.ebi.ac.uk/ena/data/ view/PRJEB15197).The authors declare that the data supporting the findings of this study are available within the article, it supplementary files, and upon request.
In the association analysis, we adjusted for sex determined from genotype data.
In the association analysis, we used data on individuals of European descent.We used linkage disequilibrium (LD) score regression to account for distribution inflation in the dataset due to cryptic relatedness and population stratification.
The Icelandic dataset is based on whole-genome sequence data from 63,460 Icelanders participating in various research projects at deCODE genetics.Variants identified through whole-genome sequencing were imputed into 173,025 chip-genotyped Icelanders as well as their untyped close relatives based on genealogy.The Swedish dataset is based on whole-genome sequence data of 17,408 individuals of European origin, including 3,704 Swedes participating in various research projects at deCODE.The sequence genotypes were phased with chip genotypes and 170 million variants identified in the whole-genome sequencing were imputed into the phased chip data.
For the Icelandic and Swedish dataset individuals were recruited through various research projects at deCODE genetics.Specific for this project, the IgG subclass concentrations for the Icelanders were obtained from clinical laboratories for 2,585 adults aged 18 to 92 years, as well as for 4,371 children and adolescents under 18 years.To generate the Swedish data set, we measured IgG subclass concentrations in 1,749 adult blood donors.
The study was approved by the National Bioethics Committee in Iceland (Approval no.15-023) following a review by the Icelandic Data Protection Authority.All participating subjects who donated blood signed informed consent.The personal identities of the participants and biological samples were encrypted using a third-party system approved and monitored by the Icelandic Data Protection Authority.The Swedish samples were collected subject to ethical approval (Lund University Ethical Review Board, dnr 2013/54).
The samples size corresponds to the available data from Iceland and Sweden Icelandic individuals with known diagnosis of multiple myeloma, nonoclonal gammopathy of unknown significance, Waldenström's disease, lymphoid malignancies, liver cirrhosis or primary biliary cirrhosis in deCODE's phenotype database were excluded.No other available data was excluded from the analyzes.
We performed GWAS studies in two independent populations and combined the results.Results are presented for the populations independently and combined and heterogeneity of effects between gopus are assessed.

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April 2023
Reporting for specific materials, systems and methods We require information from authors about some types of materials, experimental systems and methods used in many studies.Here, indicate whether each material, system or method listed is relevant to your study.If you are not sure if a list item applies to your research, read the appropriate section before selecting a response.The axis labels state the marker and fluorochrome used (e.g.CD4-FITC).

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The axis scales are clearly visible.Include numbers along axes only for bottom left plot of group (a 'group' is an analysis of identical markers).
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A numerical value for number of cells or percentage (with statistics) is provided.
EasySep magnetic cell sorting (StemCell Technolocies, cat. # 19674, 19662, and 19663 respectively) EasySep magnetic cell sorting is quality control tested by the manufacturer as stated on their website https://www.stemcell.com/different plasma cell lines (MOLP8, L363 and RPMI8226), HEK cells Describe the authentication procedures for each cell line used OR declare that none of the cell lines used were authenticated.
Confirm that all cell lines tested negative for mycoplasma contamination OR describe the results of the testing for mycoplasma contamination OR declare that the cell lines were not tested for mycoplasma contamination.
Name any commonly misidentified cell lines used in the study and provide a rationale for their use.
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